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Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.
Kim, H R; Kang, H N; Shim, H S; Kim, E Y; Kim, J; Kim, D J; Lee, J G; Lee, C Y; Hong, M H; Kim, S-M; Kim, H; Pyo, K-H; Yun, M R; Park, H J; Han, J Y; Youn, H A; Ahn, M-J; Paik, S; Kim, T-M; Cho, B C.
Afiliação
  • Kim HR; Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul.
  • Kang HN; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Shim HS; Departments of Pathology.
  • Kim EY; Pulmonology, Yonsei University College of Medicine, Seoul.
  • Kim J; Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul.
  • Kim DJ; Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul.
  • Lee JG; Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul.
  • Lee CY; Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul.
  • Hong MH; Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul.
  • Kim SM; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Kim H; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Pyo KH; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Yun MR; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Park HJ; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Han JY; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Youn HA; JE-UK Institute for Cancer Research, JEUK Co, Ltd, Gumi-City, Kyungbuk.
  • Ahn MJ; Division of Hematology & Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Paik S; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul.
  • Kim TM; Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • Cho BC; Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul.
Ann Oncol ; 28(6): 1250-1259, 2017 Jun 01.
Article em En | MEDLINE | ID: mdl-28460066
ABSTRACT

BACKGROUND:

We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).

METHODS:

The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.

RESULTS:

The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.

CONCLUSIONS:

FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzimidazóis / Carcinoma de Células Escamosas / Biomarcadores / Ensaios Clínicos como Assunto / Receptores de Fatores de Crescimento de Fibroblastos / Quinolonas / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzimidazóis / Carcinoma de Células Escamosas / Biomarcadores / Ensaios Clínicos como Assunto / Receptores de Fatores de Crescimento de Fibroblastos / Quinolonas / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article